EP1664054B1 - Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin - Google Patents

Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin Download PDF

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Publication number
EP1664054B1
EP1664054B1 EP04762302A EP04762302A EP1664054B1 EP 1664054 B1 EP1664054 B1 EP 1664054B1 EP 04762302 A EP04762302 A EP 04762302A EP 04762302 A EP04762302 A EP 04762302A EP 1664054 B1 EP1664054 B1 EP 1664054B1
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Prior art keywords
ethyl
piperidino
mol
hydroxycamptothecin
carbonyloxycamptothecin
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EP04762302A
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German (de)
French (fr)
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EP1664054A1 (en
Inventor
Petr Dobrovolny
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Pliva Lachema AS
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Pliva Lachema AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This invention relates to a method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin of formula I
  • the present invention relates to a method of manufacturing of 7-ethyl-10-[4-(1-piperidino)--1-piperidino]-carbunyloxycamptothecin of formula I, characterized in that 7-ethyl--10-hydroxycamptothecin of formula II is condensed with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula III in a polar aprotic solvent such as acetonitrile and in the presence of 4-dimethylaminopyridine.
  • a polar aprotic solvent such as acetonitrile
  • the condensation proceeds in suspension, where the polar aprotic solvent dissolves only 4-dimethylaminopyridine whereas 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in this polar aprotic solvent remain undissolved.
  • the amount of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride employed in the condensation reaction is preferably 1.3 to 3 mol, more preferably 1.6 to 1.9 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin.
  • the amount of 4-dimethylaminopyridine used in the condensation ranges preferably between 1.5 and 4 mol, more preferably between 1.8 and 2.2 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin.
  • the amount of the polar aprotic solvent used in the condensation is preferably 400 to 600 mol, more preferably 430 to 460 mol, per mol of 7-ethyl-10-hydroxycamptothecin.
  • the condensation is performed preferably at a temperature from 70 to 80 °C, more preferably at 73 to 77 °C.
  • the present ballast compounds consisting of e.g. 4-dimethylaminopyridine, 4-piperidinopiperidine and urea, are removed by washing of the obtained irinotecan base by a polar aprotic solvent, preferably acetonitrile.
  • the yield of the condensation is at least 94 % and the obtained product contains at least 98 % of the desired irinotecan base, as determined by high-performance liquid chromatography.
  • the main advantage of the method according to this invention consists in that the work-up of the reaction mixture after condensation proceeds only with negligible losses of the final product and that the condensation is not accompanied with coloured impurities.
  • the obtained solution is then added quantitatively to the suspension of 7-ethyl-10-hydroxy-camptothecin.
  • Into the empty beaker are then added 13.6 g (0.0434 mol) of 1-chlorocarbonyl--4-piperidinopiperidine hydrochloride and 79 ml of acetonitrile and the suspension is stirred in the sonication bath until homogeneous.
  • the obtained suspension is transferred quantitatively into the three-necked Keller flask already containing 7-ethyl-10-hydroxycamptothecin and 4-dimethylaminopyridine in acetonitrile, and 382 ml of acetonitrile is added to the mixture.
  • the obtained reaction suspension in the Keller flask is stirred at 75 °C for 5 h. After 2 h the lightly yellow suspension becomes thicker and its colour turns into a coffee-white one, indicating thus correct course of the reaction. After 5 h, the suspension is cooled to 18 to 20 °C, filtered and the filtration cake is washed with 300 ml of acetonitrile. After removing the acetonitrile by suction filtration, the obtained 7-ethyl--10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin is dried at 60 to 65 °C to constant weight in a drier.

Abstract

The invention relates to the method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin by condensation of 7-ethyl-10-hydroxycamptothecin with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in a polar aprotic solvent in the presence of 4-dimethylaminopyridine.

Description

    Field of the Invention
  • This invention relates to a method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin of formula I
    Figure imgb0001
  • 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, which is also known as irinotecan base, is used for manufacturing of the cytostatically active irinotecan hydrochloride trihydrate, a topoisomerase inhibitor which is used in treatment of lung and rectum cancer.
    • Background of the Invention
  • 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin has been hitherto prepared by condensation of 7-ethyl-10-hydroxycamptothecin of formula
    Figure imgb0002
     with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula
    Figure imgb0003
     in pyridine at room temperature. This method has been described in the following documents: US 4,604,463 (T. M. Kanagawa, S. Sawada, K. Nokata, E- Sugino, M. Mutai), issued on August 5, 1986 ;
    S. Sawada, S. Okajima, R. Aiyama, K. Nokata, T. Furuta, T. Yokokura, E. Sugino, K. Yamachuchi, T. Miyasaka, Chemical and Pharmaceutical Bulletin 1991, 39(6), 1446-1454;
    WO 96/31513 (K. E. Henegar, J. C. Sih), published on October 10, 1996 ;
    US 6,235,907 (K. E. Henegar, J. C. Sih), issued on May 22, 2001 ;
    US 6,444,820 (K. E. Henegar, J. C. Sih), issued on September 3, 2002 .
    However, this method of preparation of irinotecan base suffers from the fact that in the condensation coloured impurities are formed which have to be removed by adsorption on a silica gel column and subsequent recrystallization from ethanol. These purification steps are accompanied by substantial losses of the final product and its yields are only about 64 %. Moreover, the method requires distillation of pyridine, extraction of a chloroform layer with sodium carbonate and sodium chloride solutions, and drying of the chloroform layer over magnesium sulfate. Therefore, a better method of preparation of irinotecan base was needed. Such a goal has been achieved by the method according to the present invention.
    • Summary of the Invention
  • The present invention relates to a method of manufacturing of 7-ethyl-10-[4-(1-piperidino)--1-piperidino]-carbunyloxycamptothecin of formula I, characterized in that 7-ethyl--10-hydroxycamptothecin of formula II
    Figure imgb0004
     is condensed with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula III
    Figure imgb0005
     in a polar aprotic solvent such as acetonitrile and in the presence of 4-dimethylaminopyridine. The condensation proceeds in suspension, where the polar aprotic solvent dissolves only 4-dimethylaminopyridine whereas 7-ethyl-10-hydroxycamptothecin and 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride in this polar aprotic solvent remain undissolved. The amount of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride employed in the condensation reaction is preferably 1.3 to 3 mol, more preferably 1.6 to 1.9 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of 4-dimethylaminopyridine used in the condensation ranges preferably between 1.5 and 4 mol, more preferably between 1.8 and 2.2 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin. The amount of the polar aprotic solvent used in the condensation is preferably 400 to 600 mol, more preferably 430 to 460 mol, per mol of 7-ethyl-10-hydroxycamptothecin. The condensation is performed preferably at a temperature from 70 to 80 °C, more preferably at 73 to 77 °C.
  • After end of the condensation, the present ballast compounds, consisting of e.g. 4-dimethylaminopyridine, 4-piperidinopiperidine and urea, are removed by washing of the obtained irinotecan base by a polar aprotic solvent, preferably acetonitrile. The yield of the condensation is at least 94 % and the obtained product contains at least 98 % of the desired irinotecan base, as determined by high-performance liquid chromatography.
  • The main advantage of the method according to this invention consists in that the work-up of the reaction mixture after condensation proceeds only with negligible losses of the final product and that the condensation is not accompanied with coloured impurities.
    • Examples Example 1
  • Into a beaker in a sonication bath are placed 10 g (0.0247 mol) of 7-ethyl-10-hydroxy-camptothecin and 99 ml of acetonitrile. The obtained suspension is stirred in the sonication bath to homogeneity. Then the suspension is transferred quantitatively into a three-necked Keller flask equipped with a mechanical stirrer, thermometer and reflux condenser. Into the now empty beaker are now placed 6.2 g (0.0502 mol) of crystalline 4-dimethylaminopyridine and 40 ml of acetonitrile. The mixture is stirred until the crystalline portion dissolves. The obtained solution is then added quantitatively to the suspension of 7-ethyl-10-hydroxy-camptothecin. Into the empty beaker are then added 13.6 g (0.0434 mol) of 1-chlorocarbonyl--4-piperidinopiperidine hydrochloride and 79 ml of acetonitrile and the suspension is stirred in the sonication bath until homogeneous. The obtained suspension is transferred quantitatively into the three-necked Keller flask already containing 7-ethyl-10-hydroxycamptothecin and 4-dimethylaminopyridine in acetonitrile, and 382 ml of acetonitrile is added to the mixture. The obtained reaction suspension in the Keller flask is stirred at 75 °C for 5 h. After 2 h the lightly yellow suspension becomes thicker and its colour turns into a coffee-white one, indicating thus correct course of the reaction. After 5 h, the suspension is cooled to 18 to 20 °C, filtered and the filtration cake is washed with 300 ml of acetonitrile. After removing the acetonitrile by suction filtration, the obtained 7-ethyl--10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin is dried at 60 to 65 °C to constant weight in a drier. This affords 14.1 g (yield 94.3 %) of product which, according to high-performance liquid chromatography, contains 98.9 % of 7-ethyl-10-[4-(1-piperidino)--1-piperidino]-carbonyloxycamptothecin.

Claims (5)

  1. A method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin of formula I
    Figure imgb0006
     characterized in that 7-ethyl-10-hydroxycamptothecin of formula II
    Figure imgb0007
     is subjected to a condensation reaction with 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of formula III
    Figure imgb0008
     in a polar aprotic solvent, e.g. in acetonitrile, in the presence of 4-dimethylaminopyridine.
  2. The method according to claim 1, characterized in that 1-chlorocarbonyl--4-piperidinopiperidine hydrochloride is employed in an amount of 1.3 to 3 mol, preferably in an amount of 1.6 to 1.9 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin.
  3. The method according to any of the preceding claims, characterized in that 4-dimethylaminopyridine is employed in an amount of 1.5 to 4 mol, preferably in an amount of 1.8 to 2.2 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin.
  4. The method according to any of the preceding claims, characterized in that the polar aprotic solvent is employed in an amount of 400 to 600 mol, preferably in an amount of 430 to 460 mol, per 1 mol of 7-ethyl-10-hydroxycamptothecin.
  5. The method according to any of the preceding claims, characterized in that the condensation reaction is carried out at a temperature of 70 to 80 °C, preferably at a temperature of 73 to 77 °C.
EP04762302A 2003-08-26 2004-08-24 Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin Active EP1664054B1 (en)

Priority Applications (1)

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PL04762302T PL1664054T3 (en) 2003-08-26 2004-08-24 Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin

Applications Claiming Priority (2)

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CZ20032305A CZ299329B6 (en) 2003-08-26 2003-08-26 Process for preparing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin
PCT/CZ2004/000050 WO2005019223A1 (en) 2003-08-26 2004-08-24 Method of manufacturing of 7-ethyl-10-[4-(1-piperidino)­-1- piperidino]- carbonyloxycamptothecin

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EP1664054B1 true EP1664054B1 (en) 2009-12-02

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US (1) US7507825B2 (en)
EP (1) EP1664054B1 (en)
AT (1) ATE450539T1 (en)
AU (1) AU2004266752A1 (en)
CZ (1) CZ299329B6 (en)
DE (1) DE602004024422D1 (en)
ES (1) ES2337578T3 (en)
HR (1) HRP20100112T1 (en)
PL (1) PL1664054T3 (en)
RU (1) RU2334748C2 (en)
WO (1) WO2005019223A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ299329B6 (en) 2003-08-26 2008-06-18 Pliva-Lachema A.S. Process for preparing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin
CZ299593B6 (en) 2003-12-16 2008-09-10 Pliva-Lachema A. S. Process for preparing 7-ethyl-10-hydroxycamptothecine
EP1803725A1 (en) 2005-12-13 2007-07-04 W.C. Heraeus GmbH Methods for preparing irinotecan
US8546573B2 (en) * 2009-11-18 2013-10-01 Cadila Healthcare Limited Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperdino] carbonyloxy-camptothecin hydrochloride trihydrate
WO2012032531A1 (en) * 2010-09-06 2012-03-15 Avra Laboratories Pvt. Ltd. Process for the manufacture of irinotecan hydrochloride by total synthesis
CN102260272B (en) * 2011-08-12 2016-01-13 扬子江药业集团有限公司 A kind of method preparing U 101440E
CN102627653B (en) * 2012-03-20 2014-10-29 南京臣功制药股份有限公司 Preparation method of irinotecan hydrochloride
EP2881396A1 (en) * 2013-12-03 2015-06-10 Synbias Pharma AG Method for the synthesis of irinotecan

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3894029A (en) * 1971-08-26 1975-07-08 Basf Ag Production of camptothecin and camptothecin-like compounds
JPS5198300A (en) * 1975-02-20 1976-08-30 Kanputoteshin oyobi sonoruijitaino seizoho
US4399282A (en) * 1979-07-10 1983-08-16 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives
US4383431A (en) 1980-11-03 1983-05-17 The Perkin-Elmer Corporation Auto-zero system for pressure transducers
US4399276A (en) * 1981-01-09 1983-08-16 Kabushiki Kaisha Yakult Honsha 7-Substituted camptothecin derivatives
US4473692A (en) * 1981-09-04 1984-09-25 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives and process for preparing same
JPS5839685A (en) 1981-09-04 1983-03-08 Yakult Honsha Co Ltd Novel camptothecin derivative and its preparation
JPS58154582A (en) 1982-03-10 1983-09-14 Yakult Honsha Co Ltd Novel camptothecin derivative and its preparation
JPS6019790A (en) * 1983-07-14 1985-01-31 Yakult Honsha Co Ltd Novel camptothecin derivative
FR2560442B1 (en) 1984-02-24 1987-08-07 Thomson Csf SLOT LINE SWITCHING AND LIMITING DEVICE, OPERATING IN MICROWAVE
FR2560315B1 (en) 1984-02-29 1990-05-18 Dba AUTOMATIC GAME RETRIEVAL DEVICE FOR CLUTCH
JPS6150985A (en) * 1984-07-05 1986-03-13 Yakult Honsha Co Ltd Novel camptothecin derivative
CA1332413C (en) * 1987-06-25 1994-10-11 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives and process for preparing same
JPH0615547B2 (en) * 1988-01-20 1994-03-02 株式会社ヤクルト本社 Novel camptothecin derivative
SK283693B6 (en) * 1990-09-28 2003-12-02 Smithkline Beecham Corporation Process for preparation of camptothecin or pharmaceutically acceptable salt thereof
GB9402934D0 (en) * 1994-02-16 1994-04-06 Erba Carlo Spa Camptothecin derivatives and process for their preparation
US5491237A (en) * 1994-05-03 1996-02-13 Glaxo Wellcome Inc. Intermediates in pharmaceutical camptothecin preparation
JPH0873461A (en) * 1994-09-06 1996-03-19 Yakult Honsha Co Ltd Novel camptothecin derivative, method for producing the same and antitumor agent
TW438775B (en) 1995-04-07 2001-06-07 Pharmacia & Upjohn Co Llc Novel intermediates and process for the manufacture of camptothecin derivatives (CPT-11) and related compounds
JP4094710B2 (en) * 1997-11-06 2008-06-04 株式会社ヤクルト本社 New camptothecin derivatives
AU4564200A (en) * 1999-04-29 2000-11-17 Aventis Pharma S.A. Method for treating cancer using camptothecin derivatives and 5-fluorouracil
AR027687A1 (en) * 2000-03-22 2003-04-09 Yakult Honsha Kk PROCEDURE TO PREPARE CAMPTOTECHINE
TWI245768B (en) * 2001-02-21 2005-12-21 Yakult Honsha Kk Process for synthesizing camptothecin related compound(s)
CZ20022250A3 (en) * 2002-06-27 2004-02-18 Pliva-Lachema A. S. Process for preparing irinotecan
CN100344633C (en) 2003-05-12 2007-10-24 台湾神隆股份有限公司 Process for the preparation of 7-alkyl-10-hydroxy-20(s)-camptothecin
CZ299329B6 (en) 2003-08-26 2008-06-18 Pliva-Lachema A.S. Process for preparing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin
CZ299593B6 (en) 2003-12-16 2008-09-10 Pliva-Lachema A. S. Process for preparing 7-ethyl-10-hydroxycamptothecine
US20050272757A1 (en) * 2004-06-04 2005-12-08 Phytogen Life Sciences Inc. Process to prepare camptothecin derivatives and novel intermediate and compounds thereof

Also Published As

Publication number Publication date
ATE450539T1 (en) 2009-12-15
RU2006109481A (en) 2006-07-27
ES2337578T3 (en) 2010-04-27
US20060199961A1 (en) 2006-09-07
US7507825B2 (en) 2009-03-24
AU2004266752A1 (en) 2005-03-03
HRP20100112T1 (en) 2010-12-31
EP1664054A1 (en) 2006-06-07
CZ299329B6 (en) 2008-06-18
CZ20032305A3 (en) 2005-04-13
RU2334748C2 (en) 2008-09-27
DE602004024422D1 (en) 2010-01-14
WO2005019223A1 (en) 2005-03-03
PL1664054T3 (en) 2010-06-30

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